Studies of protein denaturation provide critical information concerning the forces that stabilize protein structure and other assemblies. This has a significant effect on our general understanding of the structure/function aspects of proteins that will directly impact our understanding of many diseases that are related to protein unfolding, misfolding, and aggregation. While the vast majority of studies have focused on the native state of proteins, the role of the denatured state is of equal importance. It is now generally accepted that the denatured state ensemble (DSE) is not random in nature but can possess residual native and non-native structure. While our knowledge of the properties of the native state has been advanced by a variety of experimental and simulation results, our understanding of the denatured state remains somewhat simplistic primarily due to the difficulties obtaining atomic level data from experiment, and our inability to determine the thermodynamic properties of the DSE from simulation. It is proposed that a combination of recent theoretical developments using Fluctuation Solution Theory, coupled with computer simulation approaches, can provide reliable data concerning the similarities and differences between denatured states generated by changes in pressure, temperature and composition at the residue level. There are three major aims to the proposed project. Aim 1: To Determine Residue Based Contributions to Protein Thermodynamics. Aim 2: To Determine the Thermodynamic Properties of Amylin and Mutant Amylin DSEs. Aim 3: To Determine the Effects of Environment on the Thermodynamic and Aggregation Properties of Small Peptide Sequences Derived from Amylin. The results of these studies will provide valuable information concerning the nature of the denatured state and the consequences for the role the DSE may play in a variety of diseases.